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LIPID METABOLISM

LIPID METABOLISM. BY Dr OJ Tsotetsi. Lipid Metabolism. Lipid Metabolism. Where & when are fatty acids synthesized?. Synthesis of Fatty Acids (FA) occurs primarily in the liver and lactating mammary gland, less so in adipose tissue

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LIPID METABOLISM

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  1. LIPID METABOLISM BY Dr OJ Tsotetsi

  2. Lipid Metabolism

  3. Lipid Metabolism

  4. Where & when are fatty acids synthesized? • Synthesis of Fatty Acids (FA) occurs primarily in the liver and lactating mammary gland, less so in adipose tissue • FA are synthesized from acetyl CoA derived from excess protein and carbohydrate • FA synthesis uses ATP and NADPH as energy sources

  5. FA synthesis requireslots of acetyl CoA • Transfer of acetyl CoA from mitochondria to cytosol involves the citrate shuttle • Occurs when citrate concentration in mitochondria is high due to inhibition of isocitrate dehydrogenase by high levels of ATP. (Note: High ATP levels are also required for FA synthesis.)

  6. First step in FA synthesis is synthesis of malonyl CoA • Energy to form C-C bonds is supplied indirectly by synthesizing malonyl CoA from acetyl CoA using ATP and CO2 • The reaction is catalyzed by Acetyl CoA carboxylase

  7. FA synthesis • After 7 cycles, palmitoyl-S-ACP is produced and palmitate is released by palmitoyl thioesterase • Overall reaction is: 8 acetyl CoA + 14 NADPH + 14H+ + 7ATP palmitate + 8CoA + 14 NADP+ + 7ADP + 7 Pi + 7H2O

  8. FA synthesis • Further elongation and desaturation of palmitate and dietary FAs (if required) occurs in mitochondria and ER by diverse enzymes

  9. FA synthesis • Sources of NADPH for FA synthesis are the hexose monophosphate pathway and the malic enzyme reaction that converts malate to pyruvate + NADPH in the cytosol

  10. Fatty Acid Oxidation

  11. Beta-oxidation of fatty acids • β-oxidation of FA produces acetyl CoA and NADH and FADH2, which are sources of energy (ATP) • First, FA are converted to acyl CoA in the cytoplasm:

  12. Where does beta-oxidation of fatty acids take place?

  13. Carnitine shuttle • For transport into mitochondria, CoA is replaced with carnitine by acylcarnitine transferase I • Inside mitochondria a corresponding enzyme (II) forms acyl CoA • Malonyl CoA inhibits acylcarnitine transferase I • So, when FA synthesis is active, FA are not transported into mitochondria • Defects in FA transport (including carnitine deficiency) are known

  14. Reactions of beta-oxidation • The cycle of reactions is repeated until the fatty acid is converted to acetyl CoA

  15. Beta Oxidation

  16. Energy yield from beta-oxidationof fatty acids • For palmitate (16:0) the overall reaction is: Palmitate + 8CoA + 7NAD+ + 7FAD + 7H2O 8 Acetyl CoA + 7NADH + 7FADH2 + 7 H+ • Energy yield as ATP for palmitate: 7 FADH2 = 1.5 x 7 = 10.5 ATP 7 NADH = 2.5 x 7 = 17.5 ATP 8 Acetyl CoA = 10 x 8 = 80 ATP Total: 108 ATP • But, two high energy bonds used in acyl CoA formation, so overall yield is 106 ATP. Why do we subtract two ATPs?

  17. Energy yield from beta-oxidationof fatty acids • Energy yield as ATP for palmitic acid: 7 FADH2 = 1.5 x 7 = 10.5 ATP 7 NADH = 2.5 x 7 = 17.5 ATP 8 Acetyl CoA = 10 x 8 = 80 ATP Total: 108 ATP • Two high energy bonds used in acyl CoA formation, so overall yield is 106 ATP

  18. Beta-oxidation of unsaturated fatty acids • Unsaturated FA yield a bit less energy than saturated FA because they are already partially oxidized • Less FADH2 is produced

  19. Why do the Lippincott and Garrett & Grisham texts give different ATP yields for complete oxidation of palmitate? • Beta oxidation occurs in mitochondria, so NADH and FADH2 can be used directly in electron transport, and acetyl CoA can also be used directly for production of energy via TCA cycle. • Theoretical yield of ATP from NADH or FADH2: 2 ATP per FADH2 3 ATP per NADH • Energy yield as ATP for palmitic acid: 7 FADH2 = 2 x 7 = 14 ATP 7 NADH = 3 x 7 = 21 ATP 8 Acetyl CoA = 12 x 8 = 96 ATP Total: 131 ATP • Two high energy bonds used in fatty acyl CoA (palmitoyl CoA) formation, so overall yield is 129 ATP (according to the Lippincott book)

  20. Actual yield of ATP from NADH or FADH2 is thought to be lower than the theoretical yield because: – Membranes leak some H+ without forming ATP – Some of the proton gradient drives other mitochondrial processes • So, actual yield is thought to be closer to: 1.5 ATP per FADH2 2.5 ATP per NADH • Actual energy yield as ATP for palmitic acid is therefore: 7 FADH2 = 1.5 x 7 = 10.5 ATP 7 NADH = 2.5 x 7 = 17.5 ATP 8 Acetyl CoA = 10 x 8 = 80 ATP Total: = 108 ATP Minus the two high energy bonds used in fatty acyl CoA formation = 106 ATP

  21. Beta-oxidation of odd-chain fatty acids • Odd-chain FA degradation yields acetyl CoAs and one propionyl CoA • Propionyl CoA is metabolized by carboxylation to methylmalonyl CoA (carboxylase is a biotin enzyme) • Methyl carbon is moved within the molecule by methylmalonyl CoA mutase (one of only two Vitamin B12 cofactor enzymes) to form succinyl CoA

  22. Are fatty acids glucogenic? • Fatty acids are not glucogenic in animals • Why can’t we make glucose from fatty acids? • Why are the statements above only ~99% true?

  23. Ketone bodies • Excess acetyl CoA (from FA or carbohydrate degradation) is converted in liver to ketone bodies: acetoacetate, acetone, and β-hydroxybutyrate • Ketone bodies are soluble in blood and can be taken up and used by various tissues (muscle, heart, renal cortex) to regenerate acetyl CoA for energy production via the TCA cycle • Even brain can use ketone bodies as their concentrations in blood rise enough

  24. Regulation of Beta Oxidation • Largely by concentration of free fatty acids available • Malonyl CoAinhibits carnitine transferase which will inhibit entry of acyl CoA into mitochondria

  25. Ketone bodies • Acetoacetyl CoA is formed by incomplete FA degradation or by condensation of two acetyl CoAs by thiolase • Acetoacetyl CoA condenses with a third acetyl CoA to form hydroxymethylglutaryl CoA (HMG-CoA) • HMG-CoA is cleaved to produce acetoacetate + acetyl CoA • Reduction of acetoacetate to β-hydroxybutyrate, or spontaneous decarboxylation to acetone, produces the other two ketone bodies

  26. KETONE BODIES • Are an easy way of transporting the energy stored in fat from the liver to other tissues because they are soluble in the blood.

  27. In tissues that use ketone bodies, acetoacetate is condensed with CoA by transfer from succinyl CoA • acetoacetyl CoA can then be converted to two acetyl CoAs

  28. Ketone bodies • Excessive ketone bodies can be produced in diabetes mellitus or starvation (a lot of acetyl CoA in liver) • When rate of production exceeds utilization, ketonemia, ketonuria, and acidemia can result

  29. acknowledgement https://www-s.med.uiuc.edu/m1/biochemistry Medical biobhemistry

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